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Original Article the Expression of MMP19 and Its Clinical Significance in Glioma

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Original Article the Expression of MMP19 and Its Clinical Significance in Glioma Int J Clin Exp Pathol 2018;11(11):5407-5412 www.ijcep.com /ISSN:1936-2625/IJCEP0085570 Original Article The expression of MMP19 and its clinical significance in glioma Qisheng Luo1,2*, Hongcheng Luo3*, Xiaoping Chen5,6*, Peng Yan2*, Huangde Fu2, Haineng Huang2, Huadong Huang2, Chuanyu Li2, Chengjian Qin2, Chuanhua Zheng2, Lan Chuanliu2, Qianli Tang1,4 1College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China; Departments of 2Neurosurgery, 3Laboratory Medicine, 4Surgery, Affiliated Hospital of Youjiang Medical Uni- versity for Nationalities, Baise, Guangxi, China; 5Department of Neurology, Guangxi Zhuang Autonomous Region People’s Hospital, Nanning, Guangxi, China; 6Guangxi Medical University Graduate School, Nanning, Guangxi, China. *Equal contributors. Received September 16, 2018; Accepted September 25, 2018; Epub November 1, 2018; Published November 15, 2018 Abstract: Aims: The expression of phosphoglycerate kinase 1 (MMP19) is elevated in some cancers. However, the clinical features and prognostic value of glioma patients with MMP19 expression are unclear. In this study, the ex- pression level of MMP19 and the correlation between the level of MMP19 expression and the clinicopathologic data in glioma patients including survival were examined. Methods and results: Using real-time PCR, the mRNA expres- sion of MMP19 was examined in 61 fresh glioma tissues and 32 brain samples. The result indicated that MMP19 mRNA was obviously elevated in glioma tissues compared to brain tissues. Further, we observed that MMP19 mRNA was much higher in stage III patients than it was in stage I-II patients. The expression of the MMP19 protein was determined by immunohistochemical analysis in 156 paraffin-embedded glioma samples and 35 normal paraffin- embedded brain samples. The MMP19 protein level was significantly increased in glioma tissues compared to brain tissues (P = 0.008). Furthermore, we observed that a high expression of MMP19 protein was positively associated with clinical stage (P = 0.008) but did not correlate with age, gender, or histological type. An increased MMP19 protein expression was associated with poor overall survival rates (P = 0.001). A stratified analysis showed that pa- tients with high MMP19 protein expression indicated a worse prognosis occurring in WHO III-IV stages (P = 0.001). A Multivariate analysis indicated that a high expression of the MMP19 protein was an independent prognostic indi- cator of patient survival (P = 0.009). Conclusions: MMP19 is overexpressed and plays a significant role in disease progression and poor outcome in glioma patients. Keywords: MMP19, overexpression, glioma, disease progression, outcome Introduction and tumor metastasis [4-8]. Matrix metallopro- teinase-19 (MMP-19), also known as matrix Glioma is a basic type of brain tumor that com- metalloproteinase RASI, is an enzyme that in prises about one-third of all brain tumors. It humans is encoded by the MMP19 gene. In a may arise from different types of glial cells, previous study, MMP19 was reported to have a which include astrocytes, oligodendrocytes, higher expression in glioma tissues than in and ependymal cells. As with many tumors, the brain tissues [9]. However, the correlation of cause of glioma is still unknown. It affects peo- MMP19 expression with clinical features and ple from all ages, although it is more common the prognosis of glioma has never been in adults than children and is more likely to reported. occur in men than in women [1]. MMP19 is the first ATP-generating enzyme of Proteins of the matrix metalloproteinase (MMP) the glycolytic pathway family are involved in the breakdown of the extracellular matrix in normal physiological In this study, we examined the expression of processes, such as embryonic development, MMP19 and explored the correlation of MMP19 reproduction, and tissue remodeling, as well as expression with clinical features and patient in disease processes, such as arthritis [2, 3] prognosis in glioma. Our data demonstrate that MMP19 overexpression in glioma DNA polymerase, followed by 45 cycles of 95°C for 13 s, 56°C for 13 s, and 72°C for 13 s. PCR reactions for each gene were repeated three times. Immunohistochemistry Figure 1. Increased MMP19 mRNA expression was positively associated Following standard protocols, with clinical progression in Glioma. A. Increased MMP19 mRNA expression the glioma paraffin tissue sec- in glioma compared to brain tissues. B. Elevated MMP19 mRNA expression tions (3 μm thick) were depar- was positively associated with clinical progression in Glioma (I-II vs. III-IV). affinized in 100% xylene and rehydrated in a descending an elevated expression of MMP19 promotes ethanol series (100%, 90%, 80%, and 70% eth- the pathogenesis of glioma and results in a anol). Heat-induced antigen retrieval was car- poor outcome. ried out in 10 mM citrate buffer for 2 min at 100°C. A peroxidase blocking reagent contain- Materials and methods ing 3% hydrogen peroxide and serum was used to block endogenous peroxidase activity and Sample collection non-specific antigens. Samples were then incu- bated with mouse anti-human MMP19 mono- Sixty-one fresh glioma tissues, 32 fresh brain clonal antibody (1:100 dilution) (Santa Cruz tissues, 156 paraffin-embedded glioma sam- Biotechnology, Inc., Santa Cruz, CA, USA) at ples, and 35 normal paraffin-embedded brain 4°C overnight. The sections were visualized samples were collected from the Affiliated with 3,3’-diaminobenzidine, counterstained Hospital of Youjiang Medical University for with hematoxylin, mounted in neutral gum, and Nationalities between 2010 and 2014. The analyzed using a bright field microscope. paraffin-embedded glioma cases included 106 males and 50 females ranging in age from 15 Evaluation of staining to 78 years (median, 43.8 years). All specimens had a confirmed pathological diagnosis and The stained tissue sections were reviewed sep- were classified according to the World Health arately by two pathologists blinded to the clini- Organization (WHO) criteria. For the use of cal parameters and evaluated for the presence these clinical materials for research purposes, of cytoplasm staining. The staining intensity prior consent from the patients and approval was scored from 1-4 (negative expression: 1; from the Ethics Committees of this hospital weak expression: 2; positive expression: 3; were obtained. strong expression: 4). The percentage of posi- tive staining areas of the cells was defined on a RNA extraction and Real-time PCR scale of 0-3 (0: < 10%, 1: 10-25%, 2: 26-75%, and 3: > 76%). For the statistical analysis, a RNA was extracted from the glioma and brain final staining score of 0-5 and 6-7 in the cyto- tissues using Trizol (Takara, Shiga, Japan). The plasm was considered to be low or high expres- RNA was transcribed into cDNA and amplifi- sion, respectively. ed with a specific MMP19 forward primer: 5’-GGATGGTCTGGCAACATGGA-3’, The reverse Statistical analyses primer: 5’-AGTCCCATGTCACTCCCAT-3’. GAPDH gene was used as an internal control, using the Statistical analyses were performed using sense primer 5’-CGGAGTCAACGGATTTGGTCG- GraphPad Prism 5 (http://www.graphpad.com/ TAT-3’ and the antisense primer 5’-AGCCTT- company/) and SPSS 20.0 software (SPSS, CTCCATGGTGGTGAAGAC-3’. The assays were Inc., Chicago, IL, USA). A two-tailed Student’s performed in accordance with the manufactur- t-test was employed for the comparisons er’s instructions (Takara, Shiga, Japan). Cycling between two groups. A chi-square test was conditions were 95°C for 10 min to activate used to examine the correlation between the 5408 Int J Clin Exp Pathol 2018;11(11):5407-5412 MMP19 overexpression in glioma Figure 2. MMP19 protein expression in glioma (original magnification: ×400). A. Negative expression of MMP19 protein in brain tissues. B. Low expression of MMP19 protein in glioma tissues of I-II stage. C. High expression of MMP19 protein in glioma tissues of III stage. Table 1. Elevated expression of the MMP19 Results protein in lung adenocarcinoma Elevated MMP19 mRNA in glioma MMP19 protein expression N P value High Low In order to assess the role of MMP19 in glioma, Cancer 156 75 81 0.008* qRT-PCR was explored to measure MMP19 Normal 35 8 27 mRNA transcripts in 61 freshly collected *, Statistically significant. MMP19 tissues and brain tissues. Compared with the brain tissues, the glioma tissues exhib- ited higher expression levels of MMP19 mRNA Table 2. Correlation between the clinico- (P = 0.003) (Figure 1A). Further, we observed pathologic characteristics and expression of that MMP19 expression was obviously in- MMP19 in glioma creased in WHO stages III-IV compared to stag- MMP19 Protein expression Figure 1B Characteristics N es I-II ( ). High low P value Age (y) Immunohistochemistry of MMP19 < 50 74 38 36 0.521 Specific MMP19 protein staining was detected ≥ 50 82 37 45 in the cytoplasms of the brain and tumor tis- Gender sues (Figure 2A-C). MMP19 expression was sig- Male 50 26 24 0.607 nificantly elevated P( = 0.008) in the glioma tis- Female 106 49 57 sues (75/156) compared to the brain tissues Histological type (8/35) (Table 1). AT 112 59 53 0.109 The correlation between MMP19 expression OT 20 11 9 and clinicopathologic parameters Other 24 17 7 WHO A significant relationship between MMP19 pro- I-II 75 19 56 0.008* tein expression with patient age, gender, and III-IV 81 25 56 histological type in the 156 glioma cases was *, Statistically significant. not observed, but high MMP19 protein expres- sion was positively correlated with the clinical stage of the disease (Table 2; P = 0.008). expression of MMP19 and the clinicopathologic features of breast cancer. The correlation High expression of MMP19 is correlated with between the protein expression of MMP19 and poor overall survival outcome survival was performed using a Kaplan-Meier analysis with the log-rank test. A P value < 0.05 A Kaplan-Meier analysis with a log-rank test was considered statistically significant.
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